Abstract

Objective: Inhibition of histone deacetylases, well described for its anti-proliferative efficacy in vivo, was recently shown to ameliorate inflammation in experimental colitis. Since inflammatory bowel disease is associated with an increased risk of developing colon cancer, here the combined anti-inflammatory and pro-apoptotic efficacy of histone deacetylase inhibitors was studied in mouse models.

Setting: The novel histone deacetylase inhibitor ITF2357 was compared to suberoylanilide hydroxamic acid in models of experimental colitis. Effects on tumor growth were studied after treatment of mice with azoxymethane and dextran sulfate sodium, and in interleukin-10 knockout mice, respectively. Possible underlying mechanisms involving apoptosis and NF-κB activation were addressed by flow cytometry and western blot.

Results: In dextran sulfate sodium- and trinitrobenzene sulfonic acid-induced colitis, treatment with ITF2357 was superior to suberoylanilide hydroxamic acid as shown by macroscopic and histologic amelioration of inflammation, by reduced production of interferon-γ and by increased production of interleukin-10. In both models of inflammation-mediated tumorigenesis, inhibition of histone deacetylases resulted in a significant suppression of tumor growth in terms of size and number along with reduced signs of inflammation. As for potential mechanisms of ITF2357 action, increased acetylation of histone 3, reduced production of interferon-γ and enhanced apoptosis in lamina propria mononuclear cells were found to accompany a histone deactylase-dependent activation of NF-κB.

Conclusions: These results indicate that inhibition of histone deactylases can attenuate inflammation-mediated tumor growth, which is paralled by an inhibition of NF-κB. Thus histone deacetylase inhibitors provide a promising strategy that combines anti-inflammatory and pro-apoptotic modes of action.